tbuckley/cabot-search huggingface dataset:
Enzalutamide vs abiraterone in patients with prostate cancer with and without type 2 diabetes mellitus.
Authors: Amy L Shaver, Nikita Nikita, Krupa Gandhi, Swapnil Sharma, Scott W. Keith, Christopher C. Yang, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2023)

5066 Background: Estimations are that 8-18% of newly diagnosed cancer patients have Type 2 Diabetes Mellitus (T2DM). Current guidelines offer no clarification on the choice of therapy for prostate cancer (PCa) patients with T2DM. Since the comorbid PCa—T2DM population is increasing and these patients face unique challenges from adverse events requiring acute care utilization (ACU) it is important to ascertain which medication poses less of a threat of adverse events. The objective of this study was to describe the SEER-Medicare T2DM-PCa population in terms of those with and without complications and determine if T2DM influences ACU and PCa medication choice. Methods: We identified men with primary PCa treated with abiraterone (ABI, 2011) or enzalutamide (ENZ, 2012) with comorbid T2DM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1999-2019). Patients with a missing date of diagnosis, those diagnosed at death, having HMO or no continuous A and B coverage 12 months before diagnosis and 6 months continuous part D coverage before starting treatment as well as 6 months following treatment or until death were excluded. T2DM was identified using ICD-9 and ICD-10 codes. ACU was calculated utilizing the CMS Research Data Assistance Center definition focusing on emergency room visits resulting in in-patent hospitalization during the 6 months following treatment initiation. Differences in emergency room in-patient visits were evaluated using negative binomial models adjusted for age, race, SEER region, marital status, state-buyin, education, income, and modified Charlson Comorbidity Index (excluding T2DM). Results: The sample of 11,163 men included 61.8% treated with ABI and 38.2% with ENZ. We identified 3,044 (27.3%) men with T2DM, of which, 59.1% were treated with ABI and 40.8% with ENZ. Compared to those without T2DM those with T2DM had more ACU, regardless of medication, with a higher rate in the ABI than ENZ group, see table. Among diabetics, those with complications related to T2DM compared to those without also experienced a higher rate of ACU. The rate of ACU was 43% higher among those treated with ABI compared to ENZ (IRR 1.43; 95% CI 1.28, 1.61). Overall mortality (15.7% vs 10.1%, p&lt;0.01) and PCa-specific mortality (8.2% vs 5.3%, p&lt;0.01) were worse in those with T2DM treated with ABI compared to ENZ. Conclusions: Outcomes for PCA patients with T2DM are worse than for those without. ACU is higher in men treated with ABI compared to ENZ regardless of T2DM status. Given the worse outcomes for comorbid T2DM patients, further study to evaluate comorbidity management in this population is warranted. [Table: see text]
GNC-038, a tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale.
Authors: Jianxiang Wang, Junyuan Qi, Wenyu Li, Zhimin Zhai, Ping Li, Wen Zou, Muran Ding, Xue Yang, Rong Wang, Wanjing Guo, Sa Xiao, Jahan S. Khalili, Hai Zhu, Martin Sebastian Olivo, Yi Zhu
Journal: Journal of Clinical Oncology (2023)

TPS2668 Background: Bispecific T cell engagers can mediate single antigen-specific cell cytolysis, but cannot preempt clonal relapse, or modify the immunosuppressive cancer cell surfaceome. The first-in-class octavalent, CD19xCD3x4-1BBxPD-L1 tetra-specific antibody, GNC-038, functions as a CD19-specific T cell engager by mediating direct antitumor activity, but further, GNC-038 overcomes inhibition of T cells by PD-L1 based on its 4 binding sites. The antitumor activity of GNC-038 is mediated by activating CD3 and 4-1BB signaling on T cells and targeting high expression of CD19 or PD-L1 on tumor cells. Preclinical studies showed GNC-038 has robust anti-tumor activity. Considering its favorable tolerance and pharmacokinetics in cynomolgus monkeys, we developed a phase I study to investigate GNC-038 for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) and relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: Patients diagnosed with relapsed/refractory non-Hodgkin lymphoma or acute lymphoblastic leukemia are currently being enrolled in this phase I study to evaluate the safety, tolerability and pharmacokinetics of GNC-038. This study will be conducted in two phases, dose-escalation (Ia) and dose-expansion (Ib). During the dose escalation phase, R/R-NHL patients will receive GNC-038 (0.016-6 μg/kg/d) as continuous intravenous (cIV) infusion for 8 weeks. Further escalation will be conducted with step-up dosing: cIV infusion of 3.6 μg/kg/d GNC-038 will be administered during week 1 followed by higher doses on subsequent weeks (9, 13.5, 20.25 or 30 μg/kg/d). R/R-ALL patients will receive GNC-038 by cIV infusion for 8 weeks (0.016-16 μg/kg/d). During the dose-expansion phase, one or more dosages will be chosen for further investigation in specific indications. The primary endpoints are dose limiting toxicity (DLT), maximum tolerated dose (MTD), treatment emergent adverse events (TEAE) and recommended phase 2 dose (RP2D). Secondary endpoints are adverse events (AEs), pharmacokinetics, objective response rate (ORR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Exploratory endpoints are biomarker assessment, anti-drug antibody (ADA) and pharmacodynamics. The dose expansion phase (Ib) has been initiated. Clinical trial information: NCT04606433 .
CABOSUN II: Results from a phase 2, open-label, multi-center randomized study of cabozantinib (CABO) vs. sunitinib (SUN) for non-clear cell renal cell carcinoma (NCCRCC).
Authors: Andrew Johns, Matthew T Campbell, Pavlos Msaouel, Eric Jonasch, Andrew Warren Hahn, Jianjun Gao, Amishi Yogesh Shah, Sangeeta Goswami, Amado J. Zurita, Lance C. Pagliaro, Mehmet Asim Bilen, Aradhana M. Venkatesan, Priya Rao, Pheroze Tamboli, Kanishka Sircar, Rebecca Slack Tidwell, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2023)

4597 Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]
Uncovering LAG-3 related tumor immunology in renal cell carcinoma and pan-cancer evaluation.
Authors: Kimiharu Takamatsu, Nobuyuki Tanaka, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya
Journal: Journal of Clinical Oncology (2023)

e16517 Background: LAG-3 (lymphocyte activation gene 3) is of interest as a target molecule for next-generation immune checkpoint inhibitors in several solid tumors, including renal cell carcinoma (RCC). The aim of this study is uncovering the tumor immune microenvironment (TIME) of the LAG-3-dominant RCC. Methods: Firstly, we performed an automated single-cell count for immunolabelled LAG-3, TIM-3 and TIGIT and TIME evaluation panel molecules (CD3, CD8, CD39, PD1, PDL1, Ctla4, CD68, CD163, CD47, Ki67, CD73, IDO1, GLUT1, CD34 and D2-40) to 105 primary ccRCC tumor samples and created the new classification model. The TIME and clinical value of LAG-3-dominant RCC were evaluated. Secondly, The TIME features of LAG-3 dominant RCC in metastatic sites was evaluated in 47 metastatic samples. Lastly, mRNA seq data from the public cohort and clinical trial data (RCC, n = 1144, other solid cancers, n = 3691) was analyzed with the digital cytometry and evaluated whether the TIME features of LAG-3 dominant RCC are RCC-specific or applicable to other solid tumors. Results: In our cohort and our validated cohort (n = 96), the LAG-3 group had significantly shorter OS (p = 0.037 and p = 0.003). The LAG-3 high expression RCC also showed shorter OS in the TCGA RCC cohort (p = 0.016). As the result of TIME evaluation, LAG-3 dominant RCCs had statistically high level of CD8, high CD39+CD8+, and high M2 macrophages. In metastasis samples, LAG-3 dominant RCCs preserved high level of CD8, high CD39+CD8+. In public mRNA seq analysis, LAG-3 dominant RCCs showed high level of CD8, high CD8+Tregs and high M2 macrophages. High Tregs in LAG-3 dominant tumor were seen in melanoma, HCC and prostate cancer. High M2 macrophage TIME in LAG-3 dominant tumor was unique to RCC, not seen in other solid cancer. Conclusions: LAG-3 dominant RCC had poor prognosis and could exhibit a unique, immunosuppressive TIME.
Matching-adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL).
Authors: Catherine Thieblemont, Kaijun Wang, Sam Keeping, Ina Zhang, Keri Yang, Boxiong Tang, Leyla Mohseninejad
Journal: Journal of Clinical Oncology (2023)

e19527 Background: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n=60 [Noy et al., Blood 2017; Noy et al., Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU vs IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: number of prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [&gt;5cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU reduced the risk of progression (HR 0.38; 95% CI 0.21–0.69) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13–4.96). OS was comparable for ZANU and IBRU, which is consistent with expectations for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the two treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU vs IBRU in R/R MZL. [Table: see text]
Camrelizumab combined with tyrosine kinase inhibitors in the treatment of patients with advanced renal cell carcinoma: A single-center prospective exploratory study.
Authors: Jing Xu, Dongyuan Zhu
Journal: Journal of Clinical Oncology (2023)

e16522 Background: At present, both NCCN and CSCO guidelines recommend tyrosine kinase inhibitors (TKIs) or immunotherapy combined with TKIs as the first-line treatment of advanced renal cell carcinoma, but no large-scale clinical research data has been disclosed on the treatment of clear cell renal cell carcinoma with camrelizumab combined with TKIs. This study aims to explore the efficacy and safety of camrelizumab combined with TKIs in advanced renal cell carcinoma. Methods: Patients with stage Ⅳ renal cell carcinoma confirmed by histopathology, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1, previously not received systematic treatment or only received one systematic treatment regimen were included in this study. The patients received (1) camrelizumab (200 mg/time, i.v., D1, q2w) (2) sunitinib (50mg, q.d., p.o.): 4 weeks on 2 weeks off, or pazopanib (800 mg, q.d.) or axitinib (5 mg, bid), until the disease progresses, intolerable toxicity occurs or the patient dies. The primary endpoint was the objective response rate (ORR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), and the secondary endpoint was safety, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between August 21，2021，and November 10, 2022, A total of 17 patients were enrolled in the study, with an average age of 58 years old. Of all the patients included, ten (58.8%) had not received systematic treatment, and seven (41.2%) patients had received it. Of these patients, four (23.5%) patients were treated with camrelizumab combined with sunitinib, nine (52.9%) with pazopanib, four (23.5%) with axitinib. All 17 patients received at least one imaging evaluation, 11 (64.7%) patients of which had a partial response (PR) of efficacy evaluation, with an ORR of 64.7%, including 70% for first-line patients and 57.1% for second-line patients; additionally, with 3 (17.6%) cases of stable disease (SD), DCR was 82.4%; 3 (17.6%) patients of progress disease (PD). PFS has not yet been reached, with the PFS rate of 75% in 6 months and 63% in 12 months. Only three patients died, and the median OS has not reached. The main grade 3 adverse events were alanine aminotransferase (ALT) increased, Aspartate Transaminase (AST) increased, and lymphocyte count decreased, all of which were 6 cases (35.5%). No grade 4-5 adverse events occurred. Conclusions: Camrelizumab combined with TKIs in the treatment of patients with advanced renal cell carcinoma has good efficacy and controllable safety, which needs to be further verified by large-scale clinical research. Clinical trial information: ChiCTR2300068189 .
Proactive assessment of patient reported outcomes in patients with ovarian cancer.
Authors: Ainhoa Madariaga, Rodrigo Sanchez-Bayona, Lawrence Kasherman, Jose Manuel Estrada-Lorenzo, Stephanie Lheureux, Luis Manso, Pablo Tolosa Ortega, Manuel Alva Bianchi, Laura Lema, Eva M Ciruelos, David Valcarcel, Ana Oaknin, Amit M. Oza
Journal: Journal of Clinical Oncology (2023)

5567 Background: Patient reported outcome (PRO) measures are key instruments to provide an evaluation of health outcomes from the patient's perspective. Assessment of PROs may help identify the nature, severity, and time course of symptoms of concern in patients with ovarian cancer. The ability to access this information in real-time, including changes over time, could improve patient safety and decision-making. Methods: This systematic review evaluated the proactive or real-time assessment of PROs in patients with ovarian cancer undergoing systemic therapy. Medline, Embase, and Cochrane databases were searched (up to February 2022), and prospective ovarian cancer studies (experimental or observational) that incorporated PROs (including quality of life) were included. Conference abstracts were excluded. Primary objective was to assess the frequency of studies incorporating proactive use of PROs. A secondary objective was to describe PRO reporting. Descriptive statistics were used. Results: 3,071 articles were screened, with 117 included in the final analysis. Studies were published between 1990-2022 and contained 35,735 patients (median 140 patients per study; inter-quartile range 58-415). Median time from patient enrollment initiation to study publication was 7 years (range 1-15). Most studies were experimental/clinical trials (n=93, 79%), followed by observational (n=23, 20%) and not reported (n=1; Table). Among experimental studies, 56% (52/93) were phase III, 35.5% (33/93) phase II, 6.5% (6/93) phase I or I/II trials and it was not reported in two. Therapeutic strategies were assessed in 98% (91/93) of experimental studies, being the most frequent one chemotherapy (n=53, 58%), followed by antiangiogenics and PARP inhibitors (n=8, 9%, each). Types of observational studies were descriptive 43.5% (10/23), cohort 26% (6/23), cross-sectional 22% (5/23), or other 9% (2/23). PROs were the primary objective in 7.5% (7/93) and 83% (19/23) of experimental and observational studies respectively. The table describes PRO reporting standards per type of study. PROs were assessed in real-time in 0.8% (1/117) of studies. Conclusions: Completion of PRO and quality of life questionnaires involve time and effort for patients with ovarian cancer. PRO questionnaire responses were only assessed in real-time in &lt;1% of analyzed studies. Efforts should be made to incorporate proactive assessment of PROs to optimize patient care and safety. [Table: see text]
Mediators of racial/ethnic inequities in clinical trial participation among US patients with cancer, 2011-2022.
Authors: Jenny Guadamuz, Xiaoliang Wang, Ivy Altomare, Gregory Sampang Calip
Journal: Journal of Clinical Oncology (2023)

6511 Background: In 2024, the US Food &amp; Drug Administration will require drug sponsors to implement plans to improve racial/ethnic diversity in clinical trials. While minoritized populations are less likely to participate in cancer trials, it is unknown whether social determinants of health (SDOH) explain these inequities. Here we identified SDOH factors that contribute to racial/ethnic inequities in clinical trial participation among patients with 22 solid and blood cancers. Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database of adult patients with cancer (2011-2022). Area-level SDOH ( e.g., predominant race/ethnicity [proxy for segregation]) contextualizing where patients live were defined using the American Community Survey tract data. Patients were followed from cancer-specific diagnosis to clinical study drug receipt (proxy for trial participation), death, or last recorded activity. Associations of race/ethnicity and SDOH factors on trial participation were assessed using Cox proportional hazards models adjusted for clinical factors (diagnosis year, age, sex, performance status, stage, and cancer type). To elucidate which SDOH explain racial/ethnic inequities, mediation analysis was performed using nonlinear multiple additive regression trees models. Results: This study included 233,556 patients (median age: 68 years, 50.0% women; 65.6% non-Latinx [NL] White, 8.5% NL Black, 5.0% Latinx). Black and Latinx patients were more likely to live in marginalized areas ( i.e., disproportionately minoritized, low socioeconomic status, limited English proficiency, and low vehicle ownership) than White patients. Overall, 4.9% of patients participated in trials. Fewer patients from community practices or in marginalized neighborhoods participated in trials. Black (3.4%; hazard ratio [HR] 0.55, 95% confidence interval [CI]: 0.51- 0.60) and Latinx patients (3.6%; HR 0.57, CI: 0.52-0.63) were less likely to participate in trials than White patients (5.8%). Black-White trial inequities were substantially mediated (58%, CI: 47%-68%) by practice type ( e.g., community vs. academic center, 13%, CI: 10%-15%) and area-level SDOH ( e.g., segregation [33%, CI: 25%-44%] and vehicle ownership [12%, CI: 8%-15%]). Mediators explained 55% (CI: 38%-71%) of the Latinx-White trial participation inequity; area-level SDOH—including segregation (29%, CI: 13%-37%), limited English proficiency (15%, CI: 9%-25%), and vehicle ownership (8%, CI: 5%-12%)—were the most important mediators. Conclusions: SDOH factors, especially manifestations of structural racism such as segregation, explained a substantial proportion of racial/ethnic inequities in trial participation among patients with cancer. These findings can inform targeted efforts to increase racial/ethnic diversity in cancer trials.